P329: HIGH IMMUNOPROTEASOME ACTIVITY AS NOVEL INDICATOR FOR SENSITIVITY TO BORTEZOMIB-CONTAINING CHEMOTHERAPY IN ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS FROM CHILDREN’S ONCOLOGY GROUP TRIAL AALL1231
Authors: Margot Roeten, Suzanne van Dijk, Johan van Meerloo, Zinia Kwidama, Gaya Jenkins, David Teachey, Meenakshi Devidas, Mignon Loh, Gertjan Kaspers, Sonja Zweegman, Gerrit Jansen, Terzah Horton, Jacqueline Cloos
Journal: HemaSphere (2023)

Background: Previous studies showed that proteasome inhibition by bortezomib (BTZ) could be beneficial for a subset of relapsed/refractory acute leukemia (ALL) patients and that high immunoproteasome (iP) expression may serve as a biomarker for BTZ-sensitivity (Cloos et al. Cancer Metastasis Rev. 2017). Moreover, iP expression correlated with better event free survival (EFS) in newly diagnosed T-cell acute lymphoblastic leukemia patients receiving BTZ in the COG-AALL1231 trial (Roeten et al. Blood. 2022-140). However, the relationship between BTZ-sensitivity and iP activity was shown only in pre-clinical setting. Aims: In this study we investigated whether high iP activity was correlated with BTZ-sensitivity in the COG-AALL1231 phase III clinical trial (NCT02112916). Patients in arm A received augmented Berlin-Frankfurt-Munster (aBFM) therapy and patients in arm B received aBFM with BTZ. Methods: Baseline iP subunit (β1i and β5i) proteolytic activity was determined in bone marrow samples of 88 standard and intermediate risk T-ALL patients using fluorogenic substrates as previously described (Roeten et al. Cells. 2021). Minimal residual disease (MRD) measurement at end of induction (cut-off 0.01%), and EFS were used as primary and secondary outcome parameters respectively. Mann-Whitney U tests were used for between group comparisons of proteasome subunit activity and log-rank for EFS with induction failure, relapse and death (induction and remission) counted as events. Results: For 51 bone marrow samples β1i and β5i activities were measured. There was a strong correlation between β1i and β5i activity (R=0.95, P < 0.0001). For 37 samples only β5i activity could be measured due to limitations in patient material. Higher β5i activity was observed in MRDneg (<0.01%) patients from arm B compared to MRDpos (≥0.01%) patients (median 12.4 vs. 8.1 respectively, P=0.02) (Figure 1A). This difference was not found in patients who did not receive BTZ. Moreover, comparison of MRDpos patients in arm A vs arm B showed that MRDpos patients from arm B had 1.7-fold lower β5i activity compared to arm A (Figure 1B; median of 8.1 and 13.5 respectively, P=0.008). In addition, patients with high iP activity (β5i > 5.0, based on Max-stat analysis) treated with BTZ-containing chemotherapy (arm B) showed an improved EFS compared to patients with low iP activity (P=0.001). This difference in EFS was not observed in the standard therapy arm. Summary/Conclusion: These results indicate that patients with high iP activity respond well to BTZ-containing chemotherapy. Moreover, patients with high iP activity from the standard therapy arm might have benefited from the addition of BTZ, since a higher iP activity was found in MRDpos patients from standard therapy compared to BTZ-containing therapy. Altogether, this study indicates that iP activity may serve as a biomarker for BTZ-sensitivity and aid in selection of patients that may respond well to BTZ-containing chemotherapy. Follow-up studies are required to substantiate the validity of this biomarker in clinical studies.Keywords: Acute lymphoblastic leukemia, Proteasome inhibitor, Drug sensitivity, Pediatric